Functional inhibition of lactate dehydrogenase suppresses pancreatic adenocarcinoma progression.
Functional inhibition of lactate dehydrogenase suppresses pancreatic adenocarcinoma progression.
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功能性抑制乳酸脱氢酶可抑制胰腺癌进展。
DOI：
10.1002/ctm2.467
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发表时间：
2021-06
影响因子：
10.6
通讯作者：
Feng Y
中科院分区：
文献类型：
--
作者：
Cheng CS;Tan HY;Wang N;Chen L;Meng Z;Chen Z;Feng Y
胰腺癌是一种高致死性的恶性肿瘤.目前使用的临床参数可能无法准确预测临床结局，这进一步导致治疗结局不令人满意。在这项研究中，我们回顾性分析了253例PAAD患者的临床病理特征和预后。进行单变量、多变量和Kaplan-Meier生存分析，以评估风险因素和临床结局。对于功能研究，我们在PAAD细胞系中进行了乳酸脱氢酶A（LDHA）的双向遗传操作，以通过体外和体内测定来测量PAAD进展。LDHA在PAAD组织中尤其过表达，血清LDHA转录同工酶-5（LDH-5）升高与患者的临床结局较差相关。在小鼠PAAD原位模型中，LDHA的基因过表达促进了体外增殖和侵袭，以及体内肿瘤的生长和转移，而LDHA的基因敲低则表现出相反的效果。LDHA诱导的L-乳酸产生是LDHA促进PAAD进展的原因。机制上，LDHA过表达降低了PAAD细胞中代谢调节因子AMPK的磷酸化，并促进了下游mTOR的磷酸化。抑制mTOR可抑制LDHA诱导的增殖和侵袭。选择天然产物小檗碱作为LDHA的功能性抑制剂，其降低PAAD细胞中LDHA蛋白的活性和表达。小檗碱在体外抑制PAAD细胞增殖和侵袭，在体内抑制肿瘤进展。恢复LDHA可减弱小檗碱对PAAD的抑制作用。我们的研究结果表明，LDHA可能是一个新的生物标志物和潜在的治疗靶点的人PAAD。LDHA转录同工酶-5是PAAD中的一种新的血清预后生物标志物LDHA过表达与PAAD进展正相关LDHA和L-乳酸上调抑制AMPK活化和mTOR抑制小檗碱作为LDHA功能性抑制剂，抑制LDHA和L-乳酸，从而抑制PAAD进展
Pancreatic adenocarcinoma (PAAD) a highly lethal malignancy. The current use of clinical parameters may not accurately predict the clinical outcome, which further renders the unsatisfactory therapeutic outcome. In this study, we retrospectively analyzed the clinical‐pathological characteristics and prognosis of 253 PAAD patients. Univariate, multivariate, and Kaplan‐Meier survival analyses were conducted to assess risk factors and clinical outcomes. For functional study, we performed bidirectional genetic manipulation of lactate dehydrogenase A (LDHA) in PAAD cell lines to measure PAAD progression by both in vitro and in vivo assays. LDHA is particularly overexpressed in PAAD tissues and elevated serum LDHA‐transcribed isoenzymes‐5 (LDH‐5) was associated with poorer patients’ clinical outcomes. Genetic overexpression of LDHA promoted the proliferation and invasion in vitro, and tumor growth and metastasis in vivo in murine PAAD orthotopic models, while knockdown of LDHA exhibited opposite effects. LDHA‐induced L‐lactate production was responsible for the LDHA‐facilitated PAAD progression. Mechanistically, LDHA overexpression reduced the phosphorylation of metabolic regulator AMPK and promoted the downstream mTOR phosphorylation in PAAD cells. Inhibition of mTOR repressed the LDHA‐induced proliferation and invasion. A natural product berberine was selected as functional inhibitor of LDHA, which reduced activity and expression of the protein in PAAD cells. Berberine inhibited PAAD cells proliferation and invasion in vitro, and suppressed tumor progression in vivo. The restoration of LDHA attenuated the suppressive effect of berberine on PAAD. Our findings suggest that LDHA may be a novel biomarker and potential therapeutic target of human PAAD. LDHA‐transcribed isoenzymes‐5 is a novel serum prognostic biomarker in PAAD LDHA overexpression is positively correlated with PAAD progression LDHA and L‐lactate upregulation suppressed AMPK activation and inhibition of mTOR Berberine acts as a LDHA functional inhibitor, suppresses LDHA and L‐lactate and thereby represses PAAD progression
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DOI：
10.1016/s0360-3016(01)01630-3
发表时间：
2001-10-01
影响因子：
7
作者：
Brizel, DM;Schroeder, T;Mueller-Klieser, W
通讯作者：
Mueller-Klieser, W
抑制线粒体复合物 I 可改善葡萄糖代谢，与 AMPK 激活无关
影响因子：
5.3
作者：
Hou WL;Yin J;Alimujiang M;Yu XY;Ai LG;Bao YQ;Liu F;Jia WP
通讯作者：
Jia WP
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
9.9
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
通讯作者：
Chiaradonna, Ferdinando
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.